Oral tolerance (OT) is defined as the state of immunologic un- responsiveness induced by the prior feeding of antigen. Oral tolerance has been demonstrated extensively in rodents but not all species develop it, e.g., the rabbit. Because OT has never been formally demonstrated in man, we are feeding volunteers the protein antigen, keyhole limpet hemocyanin, KLH. KLH is not a common constituent to the diet and has been used safely for years as a parental immunogen to test immunocompetence. These studies have shown that KLH feeding induced systemic T cell tolerance, but at the same time primed B cells at both systemic and secretory sites. One explanation for these results is that feeding induced tolerance of Th1, but not Th2-type helper T cells. These studies were done with a single dose regimen. Little is known about the dose regimens needed to tolerize humans (but this is an important variable in rodents in the induction of OT or about the mechanisms of tolerance after protein feeding to humans. Not all proteins cause oral tolerance when fed; certain others cause immunity instead. One of the latter is cholera toxin B subunit (CT-B) which has been used to induce mucosal and systemic immunity. The reasons that one protein causes tolerance whereas another causes immunization remain obscure, but we propose that there are profound differences in the cellular and molecular responses to these two antigens when given orally and that a greater understanding of these differences is crucial. We ingest daily large amounts of antigen inthe form of food; this in essence represents "natural" oral tolerance. A previous study has shown that certain normal humans have high serum anti-OVA whereas others have low or no anti-OVA. We postulate that those with low "natural" serum antibody levels have strong oral tolerance and those with low levels have weak OT. Comparison of the two types of response will lead to an understanding of the molecular mechanisms involved OT. Moreover, the level of "natural" tolerance to food antigens may be predictive of the induction of tolerance to other fed proteins, such as autoantigens. The overall goal of this project is to understand the cellular and molecular mechanisms of mucosal tolerance and immunity in humans so that we can better exploit these in the future.